In children, autoimmune diseases and their therapies cause significant morbidity, especially in those with severe or refractory disease. The constant development of new immunosuppressants and targeted biological therapies leads to a unique 'moving target' with regard to the gold standard of treatment for these patients. However, incidental findings of cure after hematopoietic stem cell transplant (HSCT) in patients with concomitant benign or malignant hematologic disorders and autoimmune disease raise the question of whether HSCT can be used as upfront therapy for patients with severe autoimmune diseases. Animal data have been helpful in investigating both the efficacy of this modality and the mechanisms underlying cure. The potential for a therapeutic 'graft vs autoimmunity' (GVA) effect with an allogeneic approach highlights the already acknowledged need for clinical trials of allogeneic vs autologous transplant in these diseases where an autologous transplant would be the 'intuitive' albeit potentially erroneous choice. We critically review the data generated in the field thus far, and emphasize the need for an organized, interdisciplinary approach to conduct prospective clinical trials to answer these and other questions and advance the field.